Absolute Survival Advantage Research Articles

The adjuvant oxaliplatin-irinotecan paradox.

e15655 Background: A pervasive pattern in oncology is that chemotherapeutic agents which achieve acceptance for adjuvant use are the ones that have shown superior efficacy in the treatment of metastatic disease. The greater the efficacy in metastatic disease, the greater the likelihood that adjuvant use will be statistically viable. Oxaliplatin is the exception to this, having paradoxically shown similar outcomes to irinotecan in metastatic colorectal cancer (CRC) but superiority in the adjuvant setting. In this study, the TriNetX research database was used to better evaluate the adjuvant efficacy of oxaliplatin use in real-world patients. Methods: The TriNetX research database was used for this study. The TriNetX platform provides access to anonymized medical record information on more than 91 million patients in 75 large healthcare organizations. Three cohorts of stage III colorectal patients were created for comparison, utilizing International Classification of Disease-10 (ICD-10) codes and medication codes provided in the TriNetX platform. All patients were required to have a diagnosis of colon cancer (C18) and lymph node involvement (C77), with the absence of any liver or lung metastases (C78.7 and C78.0, respectively). Adjuvant oxaliplatin use was identified by the presence of the oxaliplatin medication code within 9 months of CRC diagnosis. The adjuvant oxaliplatin cohort was compared to a cohort with no oxaliplatin exposure, identified by the exclusion of the oxaliplatin medication code for 12 months following CRC diagnosis. The cohorts were balanced for age, race, gender, and ethnicity. The endpoint of the comparisons was all-cause mortality at 5 years. Results: Adjuvant use of oxaliplatin was associated with a 2.3% absolute decrease in the risk of death at 5 years (risk ratio 0.88, 95% CI (0.79,0.97), p-value 0.01). See figure 1. Conclusions: This study shows that adjuvant use of oxaliplatin is associated with a 2.3% absolute survival advantage in stage III colorectal cancer patients. This small absolute benefit is likely why occasional retrospective analyses have been unable to replicate it. A controlled interrupted time series analysis from Huang, et. al. showed no benefit to adjuvant oxaliplatin in the stage III setting for Taiwanese patients. Such a small benefit may also explain why the ACHIEVE trial found three months of adjuvant oxaliplatin to be equivalent to six. When a benefit is very small, a shorter duration of treatment would be more likely to result in statistical equivalency than if the benefit was more substantial. [Table: see text]

Gemtuzumab Ozogamicin Plus Standard Induction Chemotherapy Improves Outcomes in Intermediate Risk Cytogenetic Acute Myeloid Leukemia

Background: Gemtuzumab ozogamicin (GO) is a CD33-directed antibody-drug conjugate approved for the treatment of newly diagnosed (ND) and refractory/relapsed CD33-positive acute myeloid leukemia (AML). Meta-analysis of individual patient (pt) data from 5 randomized controlled trials (n=3325) confirmed a significant survival benefit of GO added to intensive induction chemotherapy for pts with AML without adverse cytogenetics. While favorable-risk ND-AML pts, specifically core-binding factor AML (CBF-AML), particularly benefited with a 5-year overall survival (OS) improvement of 20.7% (log rank p= 0.0006), pts with intermediate-risk AML also showed a significant 5-yr survival improvement of 5.7% (p=0.005) (Hills RK et al Lancet Oncol 2014: 15, 986). However, the smaller difference in these latter pts coupled with apprehension for risk of sinusoidal obstruction syndrome (SOS) following hematopoietic stem cell transplantation (HSCT) has led many clinicians to not use 7+3 plus GO in the intermediate-risk AML population. Aim/Objective: To perform a retrospective analysis of outcomes of 7+3 plus GO vs 7+3 in ND intermediate-risk cytogenetic AML pts treated at a single comprehensive cancer center. Methods: We studied the demographic, clinical and genetic data of intermediate risk ND-AML pts treated at Roswell Park Comprehensive Cancer Center (n=113) between 2015-2022. Conventional cytogenetics and fluorescence in situ hybridization (FISH) were performed. Genomic profiling was performed using next-generation sequencing methods (FoundationOne®CDx). Risk stratification was defined per the European LeukemiaNet (ELN)-2017 classification. 7+3 plus GO pts received at least one dose of GO 3 mg/m2 (up to one 4.5 mg vial) plus cytarabine 100 mg/m² continuous IV infusion on days 1-7, and daunorubicin 60 mg/m² IV on days 1-3 (7+3). Control pts received 7+3 alone. Prophylactic heparin was administered to prevent hepatic SOS based on institutional standards if not thrombocytopenic. Outcomes included response rate to induction, successful bridging to HSCT, relapse rate, and overall survival. Results: 113 intermediate-risk ND-AML pts were studied: 33 received 7+3 plus GO and 80 received 7+3. Median age was 57 vs. 59 years, respectively (range: 19-76 years). Moreover, there was no significant difference in the percentage of pts > 60 yrs (45% vs 48%). Gender was equally distributed. Pts treated with 7+3 plus GO had a significantly higher rate (p=0.019) of complete remission (CR) and complete remission with incomplete count recovery (CRi) (27/33, 82%) than 7+3 (44/80, 55%; Figure 1A). Among pts with available minimal residual disease (MRD) status detected by multiparameter flow cytometry, 100% achieved MRD-negative status after 7+3 plus GO (18/18) compared to 86% with 7+3 (12/14). Non-responders to 7+3 plus GO were enriched for ASXL1, DNMT3A, TET2, and TP53 mutations as compared to responders who harbored more FLT3, IDH1/2, KRAS/NRAS and RUNX1 mutations. Among pts achieving CR/CRi, 48% after 7+3 plus GO vs 30% after 7+3 (p=0.13) were successfully bridged to HSCT. Cumulative incidence of relapse after CR/CRi was significantly lower after 7+3 plus GO (11%) than 7+3 (43%; p=0.007). Finally, 7+3 plus GO pts demonstrated a superior, yet not statistically significant, median overall survival (OS) benefit (median OS not reached) compared to 7+3 alone (median OS = 35 months; Figure 1B). No pts receiving 7+3 plus GO developed SOS. Conclusions: Intermediate risk ND-AML pts treated with 7+3 plus GO at our academic center had significantly higher rates of MRD-negative CR and CRi, lower rates of relapse, and higher percentage of pts receiving HSCT as compared with 7+3 alone. Non-responders in the 7+3 plus GO group harbored adverse risk genetic mutations that likely dictated the failure to response. Although addition of GO was associated with a non-significant trend towards improved overall survival, longer follow-up is warranted to decipher an absolute survival advantage of this regimen. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Pharmacoeconomic considerations for acute myeloid leukemia pharmacotherapy

Introduction Acute myeloid leukemia (AML) is a rare blood cancer with a poor prognosis. Recently, targeted drugs have improved survival both in the elderly and in fit patients. However, as monthly costs of targeted agents are high, regulatory bodies often impose restrictions on their use. Areas Covered The authors review the value-for-cost of targeted drugs such as gemtuzumab ozogamycin, CPX-351, midostaurin, gilteritinib, glasdegib, venetoclax, oral azacytidine and enasidenib used to treat adult AML. EMBASE and TRIP databases, together with authority web sites were searched for technology assessments. Add-on drugs, namely midostaurin and gemtuzumab ozogamycin, have been reported to have the best pharmacoeconomic profile for newly diagnosed fit patients with FLT3 mutation or favorable/intermediate cytogenetics, since allogeneic transplant rates were stable or reduced. Most of the other drugs, on the other hand, did not achieve highly favorable cost-for-benefit, due to a poor absolute survival gain and/or increased transplant rates. Expert opinion The cost of most targeted therapies for AML in unfit patients seems unfair in comparison to the absolute survival advantage provided in fit patients. Point of cure and transplant outcomes should be standardized to allow comparability among the models.

The 21-gene recurrence score in node-positive, hormone receptor-positive, HER2-negative breast cancer: a cautionary tale from an NCDB analysis.

The 21-gene recurrence score assay (RS) has not been prospectively validated to predict adjuvant chemotherapy benefit in hormone receptor-positive (HR+), HER2-negative (HER2-), node-positive breast cancer patients. Nevertheless, de-escalation based on RS has been demonstrated and partially advocated by retrospective data. The purpose of this study was to identify subgroups of node-positive patients with low to intermediate RS who still benefit from adjuvant chemotherapy. The National Cancer Database was used to identify 28,591 women with stage I-III, T1-T3, N1, HR+, HER2- breast cancer and a RS ≤ 25 between 2010 and 2016. Univariate and multivariate analyses were used to identify variables correlating with chemotherapy use and 5-year survival. Subgroup analysis was performed to discern patients in whom the use of adjuvant chemotherapy correlated with better survival. A 35% decline in chemotherapy use was observed from 2010 to 2016. Patients with younger age, higher RS, larger tumors and more positive lymph nodes, and those treated by mastectomy, axillary lymph node dissection and radiation, were more likely to receive chemotherapy. Chemotherapy use was associated with an improved 5-year survival (HR = 1.63, 95% CI 1.28-2.07). Upon subgroup analysis, this association was lost in patients > 70years and those with a RS ≤ 11, while patients ≤ 70 with a RS of 12-25 treated with chemotherapy had an absolute 5-year survival advantage of 3.0% (HR = 1.91, 95% CI 1.42-2.57). Clinicians should be cautious when considering omission of adjuvant chemotherapy in patients ≤ 70years, with HR+, HER2-, N1 tumors and a RS 12-25, at least until the results of the anticipated RxPONDER trial become available.

Cardiac Events and Cardiac Monitoring in Adjuvant Trastuzumab Patients at The Christie: a Retrospective Audit

Purpose:Web-based prognostic and predictive tools are used to quantify the risk of relapse, death and absolute benefit of adjuvant chemotherapy. These decision aids include Adjuvant! Online and Predict. Validated genomic tests such as Oncotype DX quantify the individual risk profile using gene expression analysis. We assessed decision-making for adjuvant chemotherapy using Adjuvant! Online in the absence of genomic testing for ‘intermediate’ risk patients. Methods: A retrospective analysis was conducted in patients who underwent curative local breast axillary surgery between 1 April 2014 and 31 March 2015. Evaluable patients were required to have tumours that were ER positive, HER-2 negative (FISH), no lymph node involvement and any grade or size. ‘Intermediate risk’was defined as an absolute overall survival advantage between 3 and 5% at 10 years using the Adjuvant! Online tool. The treatment decision (chemotherapy or no chemotherapy) was documented. Results: 31 patients were identified with a mean age of 57.2 years (range 38e74). The mean age that received chemotherapy was 50.1 versus 61.1 who did not. Tumour size distribution was T1 (35.5%), T2 (61.3%), T3 (3.2%) and T4 (0%); grade 1 (0%), grade 2 (58%), grade 3 (42%). 11 patients (35%) received adjuvant chemotherapy. Patients who received chemotherapy were associated with high grade tumours (70% grade 3). The mean tumour size in the two groups was similar (23.2 mm [chemotherapy] versus 28.4 mm). 73% of patients who accepted adjuvant chemotherapy were quoted an overall projected survival advantage at 10 years of 5% compared with 30% in those who declined treatment. Conclusions: Currently, patients with an estimated 3e5% overall survival benefit by Adjuvant! Online are offered Oncotype DX testing. The majority of ‘intermediate risk’ patients declined adjuvant chemotherapy. Those who accepted treatmentweremore likely to have a benefit of 5% or greater. Future audits will re-evaluate chemotherapy acceptance rates and the cost-effectiveness of genomic assays.

Surveillance and Radiation Therapy for Stage I Seminoma—Have We Learned From the Evidence?

To analyze, in the setting of stage I seminoma, the factors affecting adjuvant treatment decisions and resulting survival outcomes, using a national dataset. We identified 33,094 stage I seminoma patients after orchiectomy from 1998 to 2012 from the National Cancer Data Base. Factors affecting treatment selection (active surveillance [AS] vs adjuvant treatment [AT]) were identified using a parsimonious multivariate logistic regression model. Propensity scores for treatment decision were generated and incorporated into a multivariate Cox regression analysis of overall survival. This process was then repeated within the AT cohort for factors predictive for chemotherapy [CT] versus radiation therapy [RT]. Only 33% of patients received AS, and 65% received AT (89% RT and 11% CT). From 1998 to 2012 the proportion receiving AS increased from 23% to 60%, whereas RT utilization decreased from 73% to 21%, and CT utilization increased from 2% to 17%. Utilization of low-dose RT increased from 1.5% in 1999 to 34% in 2012. There was a small absolute overall survival advantage to AT over AS at 10 years (95.0% vs 93.4%, propensity adjusted hazard ratio 0.58, P<.0005). There has been a significant increase in use of AS for stage I seminoma, influenced by both sociodemogrpahic and clinicopathologic factors. Between AT options, there has been significant increase in use of CT, mirrored by a decline in use of RT. Although overall survival remains high for all 3 treatment strategies, AT seems to be associated with a small absolute survival advantage over AS up to 10 years out from diagnosis.

The Toll-Like Receptor 5 Agonist Entolimod Mitigates Lethal Acute Radiation Syndrome in Non-Human Primates.

There are currently no approved medical radiation countermeasures (MRC) to reduce the lethality of high-dose total body ionizing irradiation expected in nuclear emergencies. An ideal MRC would be effective even when administered well after radiation exposure and would counteract the effects of irradiation on the hematopoietic system and gastrointestinal tract that contribute to its lethality. Entolimod is a Toll-like receptor 5 agonist with demonstrated radioprotective/mitigative activity in rodents and radioprotective activity in non-human primates. Here, we report data from several exploratory studies conducted in lethally irradiated non-human primates (rhesus macaques) treated with a single intramuscular injection of entolimod (in the absence of intensive individualized supportive care) administered in a mitigative regimen, 1–48 hours after irradiation. Following exposure to LD50-70/40 of radiation, injection of efficacious doses of entolimod administered as late as 25 hours thereafter reduced the risk of mortality 2-3-fold, providing a statistically significant (P<0.01) absolute survival advantage of 40–60% compared to vehicle treatment. Similar magnitude of survival improvement was also achieved with drug delivered 48 hours after irradiation. Improved survival was accompanied by predominantly significant (P<0.05) effects of entolimod administration on accelerated morphological recovery of hematopoietic and immune system organs, decreased severity and duration of thrombocytopenia, anemia and neutropenia, and increased clonogenic potential of the bone marrow compared to control irradiated animals. Entolimod treatment also led to reduced apoptosis and accelerated crypt regeneration in the gastrointestinal tract. Together, these data indicate that entolimod is a highly promising potential life-saving treatment for victims of radiation disasters.

Adjuvant Chemotherapy for Locally Advanced Rectal Cancer: Is It a Given?

Adjuvant therapy for solid tumors is designed to cure patients more often than surgery alone, and the first principles of adjuvant therapy include gaining both local and systemic control. Locally advanced rectal cancer isdefinedbyeitherT3ornodepositivity,andhistorically ithashad a high risk for both local recurrence (LR) and distant recurrence. Unlike other solid tumors, local control in rectal cancer is a worthy pursuit, even in the absence of systemic therapy, as a result of the profound morbidity associated with LR and the inability to salvage most LRs with surgery. Consequently, combined-modality therapy with chemotherapy, radiation,andsurgeryemergedinthe1980sand1990sastheoptimumtherapy for reducing the risk of both LR and distant recurrence. Adjuvant (postoperative) chemotherapy has been accepted as a component of multimodality therapy for locally advanced rectal cancer for two primary reasons. First, postoperative fluorouracil was associated with an improvement in overall survival (OS) in patients with Dukes’ B and C rectal cancer from the era preceding total mesorectal excision. Second, the relative 25% to 30% risk reduction in distant metastases and death in these studies is concordant with the benefits of adjuvant chemotherapyseenincoloncancer. Subsequently, randomizedtrials inpatients with locally advanced rectal cancer adopted as standard therapy that all patients receive fluorouracil after completion of surgery and radiation therapy.Accordingly, theNationalComprehensiveCancerNetworkVersion 2.2015 recommends the routine use of infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX) or capecitabine and oxaliplatin (CAPEOX) chemotherapy for a total perioperative therapeutic period (includingchemoradiotherapy)of6months.Inthemostcommonlyused treatment paradigm for patients with stage II or III rectal cancer, patients receive preoperative chemoradiotherapy or short-course radiation followed by total mesorectal excision (TME) which is then followed by 4 months of an adjuvant fluoropyrimidine with or without oxaliplatin. Yet the field of rectal cancer has changed substantially in three ways that make applying information from the early trials problematic. First, neoadjuvant chemoradiotherapy is routinely used now. Moreover, the downstaging effect of preoperative therapy leaves many clinicians afraid to omit postoperative chemotherapy “in case the nodes were originally positive.” Second, the adoption of TME has substantially decreased LR from 25% to 50% to less than 10%. Finally, imaging with chest-abdominal-pelvic computed tomography scans, rectal magnetic resonance imaging scans, positron emission tomography scans, and liver magnetic resonance imaging scans has caused stage migration. Many patients in the earlier studies undoubtedly had early stage IV disease and would have been excluded in modern trials. Are there any studies in the modern era that take into account these changes and support the routine use of postoperative chemotherapy in patients who received preoperative radiation therapy? The simple answer is no (Table 1). The study at the heart of this controversy is the European Organisation for Research and Treatment of Cancer (EORTC) 22921 (Radiation Therapy, Surgery, and Chemotherapy in Treating Patients With Rectal Cancer That Can Be Surgically Removed), which randomly assigned 1,011 patients with clinical stage II or III rectal cancer who were receiving preoperative radiation 45 Gy in a 2 2 factorial design to two separate chemotherapy regimens. In the first step, patients were randomly assigned to concurrent fluorouracil with preoperative radiotherapy or radiotherapy alone. In the second step, patients were randomly assigned to four cycles of adjuvant fluorouracil/leucovorin given every 3 weeks. The study was designed and powered to demonstrate an absolute 10% OS benefit. With long-term follow-up (median, 10.4 years), there was no differenceinOSat10years(51.8%[adjuvantchemotherapy]v48.4%[no chemotherapy]), disease-free survival (DFS) at 10 years (47.0% [adjuvant chemotherapy] v 43.7% [no chemotherapy]) or cumulative incidence of distant metastases (P .52). Interestingly, all three arms receiving any chemotherapy had decreased LR at 10 years (21.9% [radiotherapy alone] v11.8%to14.5%[threechemotherapyarms];P .0017),butthisdidnot translate into an OS advantage, perhaps because the trial was underpowered to determine an absolute survival advantage of less than 10%. Interestingly, the benefit of adjuvant chemotherapy in patients with ypT0-2 seen in the first analysis has disappeared. The unexpected outcome of this study led to controversy. First, the chemotherapy delivered was not the standard in the United States. The concurrent fluorouracil was given as a bolus regimen in the Mayo Clinic schedule(albeitatadosereductionof350mg/m asopposedto400to425 mg/m) rather than infusional. Adjuvant chemotherapy was given at the same dose-reduced schedule. Second, this study has been criticized for being underpowered for a four-arm comparison trial, with only 252 to 253patientsperarm.However, thestudywasdesignedasa2 2factorial trial, which allows for an appropriate comparison between the approximately500patientswhoreceivedadjuvantchemotherapycomparedwith the approximately 500 patients who did not. These numbers appropriately drove the power calculation seeking a 10% OS benefit at 5 years. Thus, although the comparison of adjuvant chemotherapy or not was appropriatelystratifiedbypreoperative treatment, thereporteddifference reflects the entire 1,011 patients randomly assigned in the intent-to-treat analysis. JOURNAL OF CLINICAL ONCOLOGY COMMENTS AND CONTROVERSIES VOLUME 33 NUMBER 17 JUNE 1

Prone Position in Acute Respiratory Distress Syndrome. Rationale, Indications, and Limits

In the prone position, computed tomography scan densities redistribute from dorsal to ventral as the dorsal region tends to reexpand while the ventral zone tends to collapse. Although gravitational influence is similar in both positions, dorsal recruitment usually prevails over ventral derecruitment, because of the need for the lung and its confining chest wall to conform to the same volume. The final result of proning is that the overall lung inflation is more homogeneous from dorsal to ventral than in the supine position, with more homogeneously distributed stress and strain. As the distribution of perfusion remains nearly constant in both postures, proning usually improves oxygenation. Animal experiments clearly show that prone positioning delays or prevents ventilation-induced lung injury, likely due in large part to more homogeneously distributed stress and strain. Over the last 15 years, five major trials have been conducted to compare the prone and supine positions in acute respiratory distress syndrome, regarding survival advantage. The sequence of trials enrolled patients who were progressively more hypoxemic; exposure to the prone position was extended from 8 to 17 hours/day, and lung-protective ventilation was more rigorously applied. Single-patient and meta-analyses drawing from the four major trials showed significant survival benefit in patients with PaO2/FiO2 lower than 100. The latest PROSEVA (Proning Severe ARDS Patients) trial confirmed these benefits in a formal randomized study. The bulk of data indicates that in severe acute respiratory distress syndrome, carefully performed prone positioning offers an absolute survival advantage of 10-17%, making this intervention highly recommended in this specific population subset.

Angiopoietin-2 may contribute to multiple organ dysfunction and death in sepsis*

: In sepsis, quiescent blood vessels become leaky and inflamed by mechanisms that are incompletely understood. We hypothesized that angiopoietin-2, a partial antagonist of the endothelium-stabilizing receptor Tie-2 secreted by endothelium, contributes to adverse outcomes in this disease. : Laboratory and animal research. : Research laboratories and Emergency Department of Beth Israel Deaconess Medical Center, Boston, MA. : Angiopoietin-2 heterozygous mice, emergency department patients. : Mice with one functional angiopoietin-2 allele developed milder kidney and lung injury, less tissue inflammation, and less vascular leakage compared to wild-type counterparts. Heterozygotes experienced >40% absolute survival advantage following two different models of sepsis (p = .004 and .018). In human subjects presenting to our emergency department with suspected infection (n = 270 combined), circulating angiopoietin-2 was markedly elevated within the first hour of clinical care. First-hour angiopoietin-2 concentrations were proportional to current disease severity (p < .0001), rose further over time in eventual nonsurvivors (p < .0001), and predicted the future occurrence of shock (p < .0001) or death (p < .0001) in the original cohort and an independent validation group. Finally, septic human serum disrupted the barrier function of microvascular endothelial cells, an effect fully neutralized by an angiopoietin-2 monoclonal antibody. : We conclude that angiopoietin-2 induction precedes and contributes to the adverse outcomes in sepsis, opening a new avenue for therapeutic investigation.

Effect of neutropenia with adjuvant epirubicin-CMF on survival in patients with node-negative or 1 to 3 node-positive rapidly proliferating breast cancer.

e11566 Background: Patients who experience at least some degree of neutropenia whilst receiving adjuvant chemotherapy for breast cancer show improved survival. Tumor proliferation is a prognostic marker in breast cancer. We therefore hypothesized that patients with rapidly proliferating breast cancer and evidence of neutropenia whilst on adjuvant chemotherapy would have a better survival than that of similar patients in whom there was no evidence of myelotoxicity. Methods: We reviewed the case notes of 173 women treated in Wide Area of Romagna cancer centers with epirubicin followed by the intravenous CMF (cyclophosphamide, methotrexate and 5-fluorouracil) regimen or the inverse sequence for rapidly proliferating breast cancer, defined by thymidine labeling index (TLI) >3%, to identify patient- and treatment-related factors influencing outcome. Results: The actuarial 5-year overall survival for these women was 94%, with the anticipated poorer outcome for those with higher TLI (≥10% vs <10%, P=0.032). There was no evidence that ER-negative tumors, HER-2 positive disease or older age at presentation resulted in poorer survival. Of note, the absolute survival advantage was confined to the 47% of patients who had grade 3/4 neutropenia (P<0.001) with respect to those with grade 0-2 neutropenia (P=0.268). Conclusions: Our results suggest that neutropenia has a greater influence on outcome than age and tumor biological factors in patients with rapidly proliferating breast cancer.

Seed mass and summer drought survival in a Mediterranean-climate ecosystem

We related seed mass to summer drought survival in a Mediterranean-climate ecosystem. Previous experimental evidence linking seed mass and survival under drought is limited and at times contradictory. We tracked summer drought survival among four families/subfamilies at a restoration site in southwestern Australia. We coupled these observations with a glasshouse experiment assessing the growth and root morphology of Acacia and Eucalyptus species, with a range of seed masses, under mild and severe drought compared with a well-watered control. Summer drought survival in the field increased with seed mass across all four families/subfamilies. Seedling root biomass and length increased with seed mass consistently across five harvests over 60 days. Initial survival of seedlings in the glasshouse increased with seed mass and decreased with drought, but there was no interaction between the two. Greater absolute root investment provides a mechanism for both short and longer-term drought survival. Within-species variation in root growth may also affect the relative versus absolute survival advantage of large-seeded species. The benefits of large seed mass for establishment under environmental hazards are often considered to be temporary. Our results show that seed mass was correlated with other traits, including root length, which in turn, increased longer-term drought survival. Traits correlated with seed mass should therefore be considered in explanations of the ecological effect of seed mass variation.

Adjuvant Chemotherapy for Non–Small-Cell Lung Cancer: A Fading Effect?

Non–small-cell lung cancer (NSCLC) is the leading cause of cancer death for men and women in most industrialized countries. Surgery is the primary treatment modality for patients with early-stage operable NSCLC. Approximately half of these patients eventually experience relapse after resection, with a twoto three-fold higher proportion of distant metastases over local recurrences. Five-year survival rates for early-stage NSCLC range from 60% to 70% in stage I, 40% to 50% in stage II, and only 25% to 30% in patients with stage IIIA tumors. The 1995 meta-analysis published by the Non–SmallCell Lung Cancer Collaborative Group suggested an absolute survival advantage at 5 years of 5% with cisplatin-based chemotherapy (hazard ratio [HR] 0.87; 95% CI, 0.74 to 1.02; P .08). However, most of the early trials were small and underpowered. In the late 1990s, larger adjuvant trials were performed, three of which demonstrated a statistically significant survival benefit from cisplatin-based chemotherapy. Absolute 5-year survival differences ranged from 4% to 15% (HR 0.69 to 0.86). In the recently updated individual data-based Medical Research Council meta-analysis and in Lung Adjuvant CisplatinEvaluation(LACE), the5-yearabsolutebenefitwithchemotherapy ranged from 4% to 5.3% (HR 0.87; 95% CI, 0.81 to 0.93; P .0000001; and HR 0.89; 95% CI, 0.82 to 0.96; P .004, respectively). In the updated Medical Research Council metaanalysis, the effect of chemotherapy in addition to surgery versus surgery alone was studied in 8,147 patients (from 30 trials), with a median follow-up of 5.3 years across all trials. In the LACE study, data were pooled from 4,584 patients in five recent randomized adjuvant cisplatin-based chemotherapy trials and reported with a median follow-up of 5.1 years (range, 3.1 to 5.9 years). On the basis of these results, postoperative cisplatin-based chemotherapy is now widely accepted as treatment for patients with NSCLC. In the current issue of the Journal of Clinical Oncology, Strauss et al report mature data from the Cancer and Leukemia Group B (CALGB) trial 9633. They randomly assigned 344 patients who underwent complete resection for stage IB (T2N0) disease to four postoperative cycles of paclitaxel (200 mg/m) and carboplatin (area under the curve 6), the most frequently used doublet chemotherapy for NSCLC in the United States, compared with surgery alone. Although the initial interim analysis for survival was positive and prompted early termination of the study, survival was no longer significantly different between the two arms after a median follow-up of 74 months (HR 0.83; 90% CI, 0.64 to 1.08; P .12. In an unplanned subgroup analysis, a benefit seemed to appear for patients with tumors 4 cm in diameter (HR 0.69; 90% CI, 0.48 to 0.99; P .043). This study highlights several issues.

In reply to Mauer et al. “Statistical methodology is crucial in prognostic factor-analysis of health-related quality of life”

I would like to thank Dr. Mauer and researchers from the European Organisation for Research and Treatment of Cancer (EORTC) [1] for their important comments on our recent publication regarding health-related quality of life (QOL) in gastric cancer patients treated with first-line chemotherapy [2]. They express their opinion that the modeling strategy lacked clear selection criteria and validation. Clearly our analysis, which was conducted in a single center on a relatively small number of patients, did not establish a definitive causal relationship between baseline QOL and survival. However, there is agreement that QOL provides an assessment of patient well-being as well as of cancer survival [3]. As clinical researchers, we share Dr. Mauer’s conclusion that the results lacked adequate validation. Although external or internal validation of our final model can be readily performed these days, bootstrap is a computationally very expensive technique. The prognostic value of social functioning in our analysis, as shown in Fig. 1, was evident (the absolute difference of 1-year mortality was 0.27; 95% confidence interval [CI] of 0.8–0.87). Patients with major comorbidities or poor performance status were excluded from our randomized trials. The absolute survival advantage, therefore, most likely overestimate the advantage in the general population of gastric cancer patients. We also emphasize that our analysis represents only a small sample of patients and that patients treated with different chemotherapy regimens were included. What is clear at this time is that pretreatment measurement of QOL could help doctors in their clinical decisions as it relates to patients’ expected survival. In addition to providing prognostic information, QOL assessment may be useful to improve communication with the patient and help doctors to design tailored supportive care based on correct identification of the overall burden of symptoms, the relative importance given to each of them by the patient, and the patient’s expectations regarding treatment efficacy. Nevertheless, our results, as well as a recently published validation study by EORTC [4], may be helpful for clinical understanding of QOL in cancer patients.

Dermcidin expression confers a survival advantage in prostate cancer cells subjected to oxidative stress or hypoxia

Dermcidin (DCD) is a candidate survival gene in breast cancer. DCD gene expression has been identified in prostate cancer cell lines and primary prostate cancer tissue. The DCD protein is composed of proteolysis-inducing factor-core peptide (PIF-CP) and the skin antimicrobial DCD-1. The aim of this work was to: (i) establish if the DCD gene confers resistance of prostate cancer cells to hypoxia and oxidative stress; (ii) identify the component of the gene transcript responsible for this effect. Site-directed mutagenesis was used to create mutant DCD vectors. PC-3M prostate cancer cells were stably transfected with pcDNA3.1+ vectors encoding the entire DCD cDNA, mutant DCD vectors, or a control empty vector. Oxidative stress was produced using menadione, glucose oxidase, or hydrogen peroxide. Cell hypoxia was induced by incubation at 0.2% oxygen. Comparison of cell growth showed a 54.5% relative-proliferative advantage for the DCD-transfected PC-3M cells compared with sham-transfected cells after 8 days of cell growth (P = 0.03). Overexpression of DCD provided upto 36% absolute survival advantage over sham-transfected cells following induction of oxidative stress or hypoxia (P = 0.004). On exposure to hypoxia or oxidative stress PC-3M cells overexpressing the entire DCD gene had upto 42% survival advantage over those transfectants lacking the PIF-CP sequence (P = 0.004). DCD and PIF-CP are proliferation and survival factors in prostate cancer cells subjected to stressors found in the prostate cancer microenvironment. Thus, DCD and specifically PIF-CP are potential targets for the treatment of prostate cancer.

Does neoadjuvant chemotherapy improve survival in patients with resectable thoracic oesophageal cancer?

A best evidence topic in cardiothoracic surgery was written according to a structured protocol. The question addressed was whether neoadjuvant chemotherapy improves survival in patients with resectable oesophageal cancer. Altogether 685 papers were identified using the below mentioned search. Nine represented the best evidence to answer the clinical question. The author, journal, date and country of publication, patient group, relevant outcomes and weaknesses were tabulated. We conclude that combining neoadjuvant chemotherapy with surgery for resectable thoracic oesophageal cancer has theoretical appeal and may offer a modest survival advantage compared to surgery alone. The most recent meta-analysis and the largest randomised trial of 804 patients demonstrated an absolute survival advantage of around 7-9% at two years which just reached statistical significance. Benefit was less clear for squamous cell carcinoma than adenocarcinoma and the second largest randomised trial did not demonstrate a significant benefit.

Justifying adjuvant chemotherapy in breast cancer: A survey of women and healthcare professionals

Aim The absolute survival gains required to make adjuvant chemotherapy acceptable to women are unknown. We questioned women and healthcare professionals on the absolute survival benefits required to make adjuvant chemotherapy acceptable. Methods A cohort of 1000 Irish women and 402 UK nurses and surgeons were invited to choose an absolute survival advantage sufficient to justify adjuvant cytotoxic chemotherapy. The non-physician cohort included women with a history of cancer, female medical healthcare professionals and women with no personal or professional experience of cancer. Results Eight hundred and thirty-five women completed the questionnaire; 769, 651 and 413 said they would accept chemotherapy for a 10%, 5% and 1% survival advantage, respectively. There was a significant difference in women's preferences depending on their personal and professional experience of cancer. Eighty-nine women had personal experience of chemotherapy and these women were more likely to accept chemotherapy for any survival advantage (88, 87 and 66 for a 10%, 5% and 1% survival advantage, respectively; p = 0.0023; Chi 2). Surgeons and nurses were less likely to accept chemotherapy for smaller absolute survival advantages. Conclusions This study confirms that women require modest absolute gains to choose adjuvant chemotherapy. The pattern of acceptance differs significantly between those with professional experience of cancer, a personal history of chemotherapy use and a history of cancer or not.

Stage II Colorectal Cancer: Lack of Prognostic Model

To the Editor: Colorectal cancer (CRC) is one of the most common malignant tumors worldwide (Gatta et al. 1998 [1], Repetto et al. 2003 [2] with the disease incidence rising along with an advanced age (Wymenga et al. 2001 [3], Franceschi et al. 2001 [4]. The overall mortality from CRC is 60%, which represents the second leading cause of cancer death in western societies. In Finland, the incidence of CRC is 25/100.000, and 20/100.000 among males and females, respectively. Annually, 1.150 new cases are detected among males and 1.200 among women, representing 9.2% and 10% of all cancer cases, respectively (Finnish Cancer Registry, 2005). On the other hand, according to Benghazi Cancer Registry, 2003 [5] the colorectal cancer in eastern part of Libya is the most second frequent cancer after lung cancer in males and breast cancer in females. The average crude incidence rate is 6.4 (male) and 5.2 (female) cases per 100,000 inhabitants, representing 10.1% of male patients and 9.3% of female patients of all cancer cases. Unfortunately, there has not been a major improvement in patient survival despite the advances made in our understanding of disease and in chemotherapy practice (Walker and Quirke, 2001[6]. Surgical cure of CRC is determined by stage of the tumor and its biological behaviour. Early CRCs can be cured with surgery alone. The decision to use adjuvant therapy to patients after curative surgical resection for stage II CRC (node-negative patients) is often difficult (Venook et al, 2004 [7] and its routine use is not recommended (Graziano and Cascinu, 2003 [8]. In future, however, these decisions may be made more rationally as we learn how to incorporate the use of molecular markers and predictors in these patients. Recent guidelines advocate considering factors such as tumor differentiation, tumor perforation, number of lymph nodes examined, and T stage when assessing the likely benefit: risk ratio. Microsatellite instability and allelic imbalance seem to be strong predictors of good and poor prognosis, respectively, and in the near future, therapeutic decision-making models are likely to be further refined by the inclusion of such molecular markers [9]. The well-known and important prognostic factors in patients with CRC are histological tumor stage (Dukes-classification) including the depth of invasion and lymph node infiltration (Phillips et al 1984 [10], Wiggers et al, 1988 [11], Rapponen et al, 1996 [12]. Molecular markers may help deciding adjuvant therapy for a subgroup of these patients. Because the 5-year survival in stage II patients is approximately 70% with surgery alone (Wang et al, 2003 [13], adjuvant therapy is not widely recommended and still no agreement exists on the use of chemotherapy for these patients (Di Fabio et al, 2004 [14]. However, it is well established that a sub-group of patients with stage II CRC are at high risk of recurrence and should be considered for adjuvant chemotherapy (Willett et al, 1999 [15]. Some studies have suggested a definite survival benefit from chemotherapy in this sub-group of node-negative patients (Venook et al, 2004). To date, most of the randomized trials have demonstrated a relative reduction in tumor recurrence but have not shown any significant impact on survival in stage II disease, however. It seems likely that this failure to demonstrate a survival benefit from adjuvant chemotherapy in stage II disease is due to the fact that these trials do not have enough statistical power due to small patient series. Nevertheless, the absolute survival advantage is only about 2% and clinicians need to weigh this against the costs and toxicities of the treatment when managing these patients (Haydon A, 2003 [16]. In brief, the main long-term goal of building up a prognostic model (index) in stage II CRC is to accurately: 1) Predict patients who are at high risk for developing recurrent disease, 2) Identify the patients among stage II cases who should benefit from adjuvant chemotherapy, and finally 3) Predict the overall disease outcome.

Chemotherapy following complete resection of non-small-cell lung cancer is of small but significant benefit in terms of survival

A best evidence topic in thoracic surgery was written according to a structured protocol. The question addressed was whether patients benefit in terms of survival from chemotherapy following complete resection of non-small-cell lung cancer. Altogether 681 papers were found using the reported search, of which 14 represented the best evidence on this topic. The author, journal, date and country of publication, patient group studied, study type, relevant outcomes, results and study weaknesses were tabulated. We conclude that post-operative adjuvant chemotherapy carries a small survival benefit in those patients with complete resection of their lung cancer. This survival benefit is in the region of a 4% absolute survival advantage at 5 years. Thus, 25 patients require chemotherapy to save one life at 5 years. This should be discussed with all the patients following complete resection of non-small-cell lung cancer.

The MRC Randomised-controlled Trial of Interferon-α, Interleukin-2 and 5-Fluorouracil vs Interferon-α Alone in Patients with Advanced Renal cell Carcinoma (RE04): Rationale and Progress

Renal cell carcinoma is diagnosed in over 6000 people, and accounts for about 2% of malignant disease annually in the UK [1]. For early stage disease, surgery with curative intent is the treatment of choice, although 30–40% of patients diagnosed with disease, apparently limited to the kidney, subsequently will relapse systemically [2]. A further 25% of patients have metastatic disease at presentation. The prognosis for metastatic renal-cell carcinoma is poor, with a median survival of 6–8 months [3]. Response rates to combination chemotherapy [4] and hormonal agents [5] have been around 5–10%. It has been known for some time that the immune system has a role in the natural history of renal-cell carcinoma. For example, spontaneous regressions are rare but well documented [6,7]. Immunotherapy with interferon (IFN) in metastatic disease produces response rates of around 10–20%, with median response durations of 3–16 months [8]. Retrospective data have also shown that patients with a performance status of 0 or 1 are more likely to gain benefit (i.e. increase in median survival) from immunotherapy than are patients with a performance status of 2 or worse [9]. Randomisedcontrolled trials have shown a survival advantage to IFN compared with non-immunotherapy. A randomised trial comparing IFN-a plus vinblastine (VLB) with VLB alone reported a median survival of about 16 months for the 79 patients receiving IFN plus VLB, and 9 months for the 81 patients treated with VLB (PZ 0.0049). Overall response rates were 16.5% for patients treated with IFN plus VLB and 2.5% for patients treated with VLB alone (PZ 0.0025) [10]. The